Paclitaxel is a diterpenoid compound which is separated from leaves and barks of taxus chinensis genus of plants. The molecule formula of paclitaxel is C47H51NO24. The molecule weight of paclitaxel is 853.94. Paclitaxel can induce tubulin to polymerize, so as to stop the mitosis of cancer cells. Paclitaxel has broad anti-tumor ability, and is mainly used for the treatment of tumors, ovarian cancer, breast cancer, pancreatic cancer, gastric cancer, lung cancer, etc. In 1992, Food and Drug Administration (FDA) approved the use of paclitaxel in treating various cancers. Up to now, more than 40 countries have approved the use of paclitaxel in treating cancers.
Docetaxel is a semisynthetic compound, which is obtained by semi-synthesizing incompetent precursor (10-deacetylbaccatin) that is extracted from European taxus chinensis. The molecule formula is C43H53NO14. The molecule weight is 807.88. The antitumor mechanism of docetaxel is the same as that of paclitaxel. Docetaxel has good curative effect for treating breast cancer, non-small cell lung cancer, pancreatic cancer, soft tissue sarcoma, gastric cancer, ovarian cancer, prostatic cancer, etc. Compared with paclitaxel, the structure of docetaxel has two modifications. First, on the site C-10 of the ring B of taxol, acetyl is replaced by carboxyl. Second, the C-13 side chain is modified. Differences of chemical structure make docetaxel and paclitaxel different in terms of activity. The cytotoxic effect of docetaxel is 1.3-12 times of that of paclitaxel.
Due to the special structure, the water solubility of taxane-typed drug is very poor, which is less than 1 μg/mL at room temperature. Thus, the key technology in the research of reagent of taxane-typed drug is to improve the solubility of taxane-typed drug in aqueous solution. Currently, liquid injection reagents and freeze-dried powder reagents are mainly and clinically used. Nowadays, liquid injection paclitaxel (Taxol®) on the market uses polyoxyethylated castor oil (Cremphor EL) and absolute ethyl alcohol as solvents, while docetaxel uses polysorbate 80 (Tween 80) and absolute ethyl alcohol as solvents. Although the solubility of the drug is increased by a certain degree, patients have severe allergic reactions, nephrotoxicity, neurotoxicity, cardiotoxicity, hypotension and other adverse reactions after the treatment. Thus, the research on the freeze-dried powder without highly poisonous organic solvent has attracted the attention of researchers.
Nowadays, there are some good methods for preparing freeze-dried powder entrapping taxane-typed drug. For example, Chinese patent application No. CN103169662, published on Jun. 26, 2013, discloses a method for preparing paclitaxel high molecular nanoparticles. This method uses a combination of either one or more of polylactic acid, polyhydroxybutanoic acid, poly (lactic acid-glycolic acid) as raw materials and uses the organic solvent to form emulsified liquid. After rotary evaporation and multiple “high-speed centrifugation-resuscitation” processes and freeze-drying, paclitaxel high-molecular nanoparticle with a particle diameter of 50-800 nm are obtained. In this method, paclitaxel and high-molecular material are just mixed physically, and the functional character of paclitaxel drug does not change. However, the process is complicated and hard to control. Since the paclitaxel and high-molecular material just interact physically, the stability is poor.
For another example, in Chinese patent application No. CN103735514, published on Nov. 25, 2015, a method for preparing nanoparticle modified by polyethylene glycol vitamin E succinate and calreticulin is disclosed. This preparation method uses phospholipids, sophorolipid, calreticulin, polyethylene glycol vitamin E succinate as raw materials, ethanol as mediate, and uses vacuum rotary evaporation to prepare nanoparticles that have an average particle diameter of 100-150 nm and can entrap hydrophobic drug such as paclitaxel, morin, apigenin and so on. In this preparation method, the process is easy to control, and the nanoparticle has a high stability. However, the components of the product obtained are complex such that there is a huge safety risk.
For another example, in Chinese patent application No. CN104490847, published on Apr. 8, 2015, a thermal denaturation method for preparing albumin nanoparticle is disclosed. This method forms stable nanoparticle by adding vanillin or the analogues and through the disulfide bond, amide bond between the albumin molecules and formation of Schiff base and other chemical bonds between albumin molecule and vanillin molecule in the heating condition. No organic solvent is introduced in the preparation process and it is safe and non-toxic. However, this method requires heating to 120° C., which may change the structure and functional feature of taxane-typed drug.
For another example, in Chinese patent application No. CN102274190, published on Dec. 5, 2012, a method for preparing paclitaxel albumin submicron is disclosed. This method uses test butyl alcohol as the emulsifier, effectively embedding paclitaxel into albumin, and uses freeze-drying method to remove tert butyl alcohol. Since carbohydrates or amino acids are used as freeze-drying protective agents in the preparation system, paclitaxel albumin submicron with stable structure is finally obtained. For this method, the process is simple, safe and non-toxic, and the product can be stored for a long time. However, the paclitaxel albumin submicron prepared by this method has a relatively large particle diameter which is 300-500 nm.
So far, paclitaxel albumin binding particles (Abraxane®) developed by Celgene Corporation, a US biopharmaceutical company, is the only nanoparticle freeze-dried powder of paclitaxel approved by FDA. This agent is prepared by using a nanoparticle albumin binding (nab) technique in ABI patent and only comprises albumin and paclitaxel without toxic solvent. This agent is suitable for treating metastatic breast cancer surviving combined chemotherapy or breast cancer relapsing within 6 months after assisted chemotherapy, advanced or metastatic non-small cell carcinoma, and metastatic pancreatic cancer. Compared with Taxol®, the solubility of paclitaxel in Abraxane® is significantly increased such that the occurrence of allergic reaction is significantly reduced. A clinical study of random control phase III for Abraxane® and Taxol® in which 454 patients participated showed that the curative effect on patients of Abraxane® is almost twice as that of Taxol®. In addition, Abraxane® does not contain toxic solvent and has a higher dose than Taxol® such that the anti-tumor effect can be improved.
Albumin is the protein existing in adtevak. Bovine serum albumin (BSA) and human serum albumin (HSA) are commonly used in researches. In addition to safety, non-toxicity, biodegradability, non-immunogenicity and other characteristics, albumin nano-carrier has its own advantages. First, as a natural transport protein, serum albumin has several drug binding sites, including hydrophobic and hydrophilic drugs. Thus, albumin nano-drug carrier has the high drug-loading capacity. Second, albumin nano-drug carrier has a natural transmembrane transport pathway and can achieve the targeted transport of the entrapped drug towards the tumor tissue. Nowadays, common methods for preparing albumin nano-carrier include anti-solvent method, emulsification method, hot gel method, nab technology, self-assembly technology, nano-spray drying, etc. Nab technology is a highly-recognized method for preparing serum albumin nano-drug carrier. In addition to Abraxane® which has been approved by FDA of the US in January 2005, there are a number of other nab technology-based drugs under development, such as ABI-008 (nab-docetaxel), ABI-009 (nab-rapamycin) and so on. However, as an ideal nano-drug carrier, albumin nanoparticle prepared by nab technology still has some disadvantages. The particle diameter of Abraxane® is 130 nm, which, strictly speaking, is not nano-size. The obtained nanoparticie prepared by such method has a poor stability and cannot survive the dilution of the buffer solution, and will aggregate into large particles within 24 hours.